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EOS Report Summary

Project ID: 279977
Funded under: FP7-IDEAS-ERC
Country: France

Final Report Summary - EOS (Enzyme catalysis in organic solvents)

Water is usually considered to be one of the most indispensable ingredients for the development of life. While living organisms can thrive in surprisingly harsh conditions – e.g. very acidic volcanic geysers or very hot and very dark hydrothermal vents – they always need water. The goal of this project was thus to identify what molecular role water plays in the functioning of biomolecules, and to use this novel insight to guide the choice of optimized conditions for enzyme catalysis in non-aqueous solvents.
The traditional picture of solvent effects on enzyme catalysis considers that the hydration layer surrounding the protein is essential to lubricate the protein motions which take place during the catalytic event. In addition, the dynamical properties of the water molecules in the biomolecular hydration shell have been suggested to differ so markedly from those of neat water that it should be considered as a different type of water, “biological water”. This picture was tentatively used to explain the measured drop in enzymatic activity with decreasing hydration levels by the increased protein rigidity. However, it fell short of guiding the choice of solvent conditions to optimize the catalytic activity, and it could not explain why certain enzyme mutants were found to exhibit enhanced activities.
In this project, we combined classical, ab initio and reactive molecular dynamics simulations with analytic modeling to elucidate the interplay between water and enzymes at a molecular level.
We first established that there is no biological water: biomolecular hydration shells exhibit dynamics which are only moderately slower than the bulk, and which can be explained by the same molecular mechanisms as the slowdown induced by non-biological solutes.
Second, we showed that although the macroscopic analogy between water and a lubricant is appealing, it is clearly not supported by our results. Adding water does not significantly change the friction over the chemical barrier. We established a molecular picture describing the effect of water on two paradigm enzymatic reactions, respectively the transesterification reaction catalyzed by subtilisin Carlsberg in a water/alkane mixture, and the hydride transfer catalyzed by dihydrofolate reductase in water/glycerol mixtures.
Enzymes are now increasingly used in non-aqueous solvents, opening a tremendous range of applications in synthetic chemistry. New, non-natural reactions involving water-insoluble reagents can be catalyzed while unwanted degradation side reactions are suppressed. However, a key challenge to these applications so far had been the greatly reduced catalytic activity compared to aqueous conditions. Our novel molecular picture of solvent effects on enzyme catalysis should provide a valuable guide to overcome these limitations and guide the choice of optimum solvent conditions with enhanced catalytic activities, of major importance for bio-catalysis in non-aqueous media.

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